ERK and USP5 govern PD-1 homeostasis via deubiquitination to modulate tumor immunotherapy

Xiangling Xiao, Jie Shi, Chuan He, Xia Bu, Yishuang Sun, Minling Gao, Bolin Xiang, Wenjun Xiong, Panpan Dai, Qi Mao, Xixin Xing, Yingmeng Yao, Haisheng Yu, Gaoshan Xu, Siqi Li, Yan Ren, Baoxiang Chen, Congqing Jiang, Geng Meng, Yu-Ru Lee, Wenyi Wei, Gordon J. Freeman, Conghua Xie () and Jinfang Zhang ()
Additional contact information
Xiangling Xiao: Wuhan University
Jie Shi: Wuhan University
Chuan He: Wuhan University
Xia Bu: Harvard Medical School
Yishuang Sun: Wuhan University
Minling Gao: Wuhan University
Bolin Xiang: Wuhan University
Wenjun Xiong: Wuhan University
Panpan Dai: Wuhan University
Qi Mao: Wuhan University
Xixin Xing: Wuhan University
Yingmeng Yao: Wuhan University
Haisheng Yu: Wuhan University
Gaoshan Xu: Wuhan University
Siqi Li: University of Copenhagen
Yan Ren: Shanghai University of Traditional Chinese Medicine
Baoxiang Chen: Zhongnan Hospital of Wuhan University
Congqing Jiang: Zhongnan Hospital of Wuhan University
Geng Meng: China Agricultural University
Yu-Ru Lee: Academia Sinica
Wenyi Wei: Harvard Medical School
Gordon J. Freeman: Harvard Medical School
Conghua Xie: Wuhan University
Jinfang Zhang: Wuhan University

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract The programmed cell death protein 1 (PD-1) is an inhibitory receptor on T cells and plays an important role in promoting cancer immune evasion. While ubiquitin E3 ligases regulating PD-1 stability have been reported, deubiquitinases governing PD-1 homeostasis to modulate tumor immunotherapy remain unknown. Here, we identify the ubiquitin-specific protease 5 (USP5) as a bona fide deubiquitinase for PD-1. Mechanistically, USP5 interacts with PD-1, leading to deubiquitination and stabilization of PD-1. Moreover, extracellular signal-regulated kinase (ERK) phosphorylates PD-1 at Thr234 and promotes PD-1 interaction with USP5. Conditional knockout of Usp5 in T cells increases the production of effector cytokines and retards tumor growth in mice. USP5 inhibition in combination with Trametinib or anti-CTLA-4 has an additive effect on suppressing tumor growth in mice. Together, this study describes a molecular mechanism of ERK/USP5-mediated regulation of PD-1 and identifies potential combinatorial therapeutic strategies for enhancing anti-tumor efficacy.

Date: 2023
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DOI: 10.1038/s41467-023-38605-3

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